Recent advances in technology have made it possible to measure directly the ionized fraction of calcium (Ca2 ion) by ion-specific electrode. My colleagues and I have recently completed studies in the open-chest dog (1,2) and in muscle bath preparations (3) that indicate that: 1) the contractile state of the heart closely parallels alterations in plasma Ca2 ion, 2) only the ionized fraction of calcium is physiologically active in tissue, 3) plasma Ca2 ion may be immediately and precisely reduced or increased by infusion of Na3 citrate or calcium salts, 4) the positive inotropic response of increasing Ca2 ion is directly related to the degree of beta-adrenergic activity, 5) calcium antagonists (D600, verapamil) exert their negative inotropic effects by acting as competitive antagonists to Ca2 ion, implying a specific Ca2 ion receptive substance (calcium receptor), and 6) there appear to be hemeostatic mechanisms that are capable of rapidly increasing or decreasing Ca 2 ion. Based on these observations I propose to: 1) explore the use of acutely altering plasma Ca2 ion in certain clinical situations, such as citrate infusions in hypercalcemic crisis and calcium-catecholamine infusion to treat pump failure in post-cardiac surgery patients, 2) investigate the role of abnormalities in plasma Ca2 ion in the pathogenesis of specific disease involving cardiac and skeletal muscle, such as myopathies and rhabdomyolysis, and 3) attempt to study in more detail the nature of homeostatic mechanisms involving rapid fluctuations in plasma Ca2 ion.